The Burkholderia cenocepacia peptidoglycan-associated lipoprotein is involved in epithelial cell attachment and elicitation of inflammation

Ruth Dennehy, Maria Romano, Alessia Ruggiero, Yasmine F. Mohamed, Simon L. Dignam, Cristobal Mujica Troncoso, Maire Callagham, Miguel A. Valvano, Rita Berisio, Siobhan McClean

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Abstract

The Burkholderia cepacia complex (Bcc) is a group of Gram-negative opportunistic pathogens causing infections in people with cystic fibrosis (CF). Bcc are highly antibiotic resistant, making conventional antibiotic treatment problematic. The identification of novel targets for anti-virulence therapies should improve therapeutic options for infected CF patients. We previously identified that the peptidoglycan-associated lipoprotein (Pal) was immunogenic in Bcc infected CF patients; however, its role in Bcc pathogenesis is unknown. The virulence of a pal deletion mutant (Δpal) in Galleria mellonella was 88-fold reduced (p<0.001) compared to wild-type. The lipopolysaccharide profiles of wild-type and Δpal were identical, indicating no involvement of Pal in O-antigen transport. However, Δpal was more susceptible to polymyxin B. Structural elucidation by X-ray crystallography and calorimetry demonstrated that Pal binds peptidoglycan fragments. Δpal showed a 1.5-fold reduced stimulation of IL-8 in CF epithelial cells relative to wild-type (p<0.001), demonstrating that Pal is a significant driver of inflammation. The Δpal mutant had reduced binding to CFBE41o- cells, but adhesion of Pal-expressing recombinant E. coli to CFBE41o- cells was enhanced compared to wild-type E. coli, confirming that Pal plays a direct role in host cell attachment. Overall, Bcc Pal mediates host cell attachment and stimulation of cytokine secretion, contributing to Bcc pathogenesis.
Original languageEnglish
Article numbere12691
JournalCellular Microbiology
Volume19
Issue number5
Early online date25 Nov 2016
DOIs
Publication statusPublished - 2017

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